Psychiatry - Theses
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ItemInflammation in psychosis: Impact on brain structure and symptoms in animal models and humans( 2019)Schizophrenia is a severe neuropsychiatric disorder, arising in adolescence and early adulthood and characterised by hallucinations, delusions, blunted affect and disorganised thought patterns. One of the most enduring features of schizophrenia and psychosis are structural brain deficits, whose pathophysiological mechanism is unknown. Accumulating evidence indicates that inflammation both peripherally and centrally in the form of increased activation of the brain’s immune cells, microglia, may be a potential cause of structural deficits in psychosis. The evidence is multi-faceted ranging from mouse models that demonstrate increased numbers of microglia, to clinical studies of patients with schizophrenia showing increased pro- inflammatory molecules within peripheral blood. However, there are still many questions that remain unanswered, including whether inflammation varies across stages of psychosis, whether it is related to structural brain deficits and symptomatology and how inflammation identified in schizophrenia relates to other candidate pathways implicated in psychosis. In this thesis a multi-disciplinary approach was adopted, considered appropriate to tackling the complexity of these questions. Firstly, to determine whether inflammation was associated with other candidate pathways implicated in psychosis, we conducted an animal study, utilising an mGluR5 KO mouse model of psychosis. Glutamate has been shown to influence neuroinflammation, with cellular studies demonstrating that mGluR5 can regulate microglial numbers and activation. At the time of conducting the study, there were no satisfactory mGluR5 PET ligands that enabled in vivo monitoring within the clinical population. The mGluR5 KO mouse had been shown to display neuropsychiatric endophenotypes related to schizophrenia and thereby offered an alternative approach to gaining further insight into the role of mGluR5 in neuroinflammation and how this may impact symptoms associated with psychosis. Our aim was to determine whether neuroinflammation, in the form of increased microglial numbers and activation was present in the mGluR5 KO mouse model thereby giving further insight as to the potential interaction of the glutamatergic system and in particular, mGluR5, with microglial homeostasis. Secondly, we aimed to determine whether peripheral inflammation was related to brain structure and clinical symptomatology. This was executed by conducting two clinical studies, that examined peripheral pro- and anti-inflammatory cytokines and complement proteins in relation to brain regional thickness and volume measurements. We used a multiplex enzyme linked immune-absorbent assays (ELISA) in serum to quantify peripheral cytokines and complement proteins across various stages of psychosis ranging from those at ultra-high risk of psychosis (UHR), to individuals experiencing their first episode (FEP) and subjects with chronic schizophrenia. We sought to determine whether circulating cytokine and complement protein levels were associated with clinical symptomatology and measurements of thickness and brain volume detected using structural magnetic resonance imaging (MRI). This thesis aimed to investigate: 1) whether mGluR5 KO mice, which demonstrate phenotypic features of schizophrenia displayed neuroinflammation in the form of increased microglial numbers when compared to their wildtype littermates 2) whether there was a relationship between cytokine or complement proteins and structural brain measurements across UHR, FEP and chronic schizophrenia 3) whether peripheral inflammatory markers (cytokine or complement proteins) were increased or decreased across stages of psychosis and examine their relationship with clinical symptoms. We found that mGluR5 KO mice have increased microglial numbers compared to WT. This agreed with our hypothesis that animals lacking mGluR5, would show higher rates of inflammation in the brain, in accordance with an anti-inflammatory effect of increased mGluR5 signalling and the psychotic endophenotype of these mice. Our findings indicate that mGluR5 may affect microglial homeostasis in the context of neurodevelopment and may impact on psychosis related behaviours exhibited by mGluR5 KO mice. Secondly, our clinical studies showed that cytokines and complement proteins were related to several brain structures implicated in psychosis, including the frontal cortex and ventricles. We revealed a positive correlation between several anti-inflammatory cytokines such as IL4 and IL13 and increases in frontal cortical thickness, which was absent in patients with psychosis. Conversely, increases in pro-inflammatory cytokine IL5 were associated with decreases in whole brain volume in FEP individuals. Thirdly, we found that while peripheral cytokines did not differ significantly between patients and controls, complement proteins were elevated in UHR and chronic schizophrenia patients. While there were no associations between cytokine proteins and clinical symptoms, we identified a molecular pattern of increased C4 and decreased C3 protein, which was associated with increases in positive and negative symptoms. Taken together, the work of this thesis suggests that inflammation is present in psychosis both in the brain and peripherally but that this depends on the proteins and stage of illness examined. Moreover, we revealed that complement proteins C3 and C4 were associated with alterations in brain structure across the combined cohort; in the case of cytokines however, the positive association between elevated anti-inflammatory cytokines and increased frontal thickness was not preserved or reversed in patient groups, indicating a potential imbalance of pro- and anti- inflammatory cytokines may influence brain structure in psychosis. Finally, we have shown that peripheral inflammation in the form of cytokine and complement proteins, may influence both brain structure and clinical symptomatology, which provides fertile ground for future longitudinal exploration of neuroinflammation in schizophrenia and psychosis.
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ItemThe neuropsychiatric disorders of focal epilepsy( 2017)Neuropsychiatric disorders commonly co-exist with focal epilepsy. Despite intense investigation there remains significant limitations to our current understanding of the aetiological relationship between these conditions, as well as the clinical and radiological factors that are associated with the development of mental illness in epileptic patients. To address these questions I assembled a large cohort of consecutive focal epilepsy patients reviewed at a large tertiary referral centre over an 11-year period, and analysed relevant clinical, radiological and demographic findings using both cross-sectional (baseline evaluation) and longitudinal (serial assessments) study designs. For cross-sectional analyses, psychiatric and epilepsy comorbidity were comprehensively identified and compared to baseline MRI-determined Deep Brain Structure (DSB) volumes. In the prospective study, standardised psychiatric and quality of life assessments were obtained in a subset of patients and the development of mental illness compared to interval changes in DSB volumes. I focus on depression and psychosis, as they represent the two most prevalent psychiatric disorders identified, and classify focal epilepsy patients according to the site of seizure origin and presence of a lesion. Contrary to the common medical belief, I found that the rates of neuropsychiatric disorders in temporal lobe epilepsy were equivalent to those in extratemporal lobe epilepsy. There were no differences between those with and without psychiatric disorder by age, gender, and laterality of seizure, epilepsy severity or duration. Patients with non-lesional epilepsy, both temporal and extratemporal, have double the rate of depression compared to those with lesional focal epilepsy. There were high rates of quality of life difficulties in people with epilepsy and comorbid psychiatric disorders but the pattern of subjective concerns does not match objective clinician ratings. The hippocampal and amygdalae volumes of epilepsy patients were reduced compared to normal controls. People with co-existing epilepsy and depression had a trend towards smaller reductions in temporal lobe structures, which may represent differential expressions of progression through inflammation, trauma or emotional processing needs with either relative sparing or volumetric increases. People with psychosis and epilepsy have bilaterally reduced hippocampi compared to those with epilepsy, where reductions are predominantly ipsilateral to seizure focus. There is less evidence for amygdala change in psychosis, but a small relative increased volume was observed compared to those with epilepsy alone. There was no evidence of progression over time at a population level over 3.9 years, although there was greater variability in size in all epilepsy subjects compared to normal controls. These results convincingly argue against assumptions about the primary role of temporal lobe foci in the pathogenesis of psychiatric comorbidities in patients with epilepsy, whilst allowing for the possibility that disruption to frontotemporal networks may be a component in the development of psychiatric disorders. Progression is not an inevitable part of the natural history, at least over a 4 year period but it is possible that individuals may exhibit marked changes. They highlight the as yet unexplored possibility that the absence of a lesion as an epileptic site may be associated with greater risks of neuropsychiatric illness and allow for speculation that this may be related to inhibitory surround impacts, more extensive underlying diffuse abnormalities and disruption to frontotemporal connectivity.
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ItemA comparison of homocysteine levels in first episode psychosis patients and age matched controls( 2007)Elevated serum homocysteine concentrations are neurotoxic and are strongly implicated as a risk factor for neuropsychiatric disease (Fabender, Mielke, Bertsch, & Hennerici, 1999; Kim & Pae, 1996; Kruman et al., 2000; Reutens & Sachdev, 2002). This study compares homocysteine levels in early stages psychosis patients and healthy controls. Data from 48 healthy controls were compared with 50 previously diagnosed psychosis patients, 15-25 years, and with a gender ratio males: females 7:3. Patients were outpatients or inpatients at ORYGEN Youth Health, with a diagnosis of first episode of psychosis defined as daily psychotic symptoms lasting longer than a week that could not be explained by other means such as “drug-induced” or “organic”. All subjects were interviewed to collect information relating to family psychotic history. A possible history of psychotic disease in control subjects was tested using the SCID Psych Screening Module, drug use recorded using Alcohol Use Disorders Identification Test (AUDIT) (for alcohol use), The Modified Fagerström Tolerance Questionnaire (mFTQ) (for smoking), Opiate Treatment Index (OTI) (for opiate-type drugs). Dietary and medication histories were also taken. Blood tests were performed to determine serum homocysteine, serum folate, red blood cell folate and serum vitamin B12 levels. An independent sample t test to compare homocysteine levels in patients and controls was performed. Serum homocysteine levels were significantly higher for patients (M = 12.9, S.D. = 3.6) than controls (M = 11.1, S.D. = 2.7) (t(96) = 2.7, p = 0.007, two-tailed). After General Linear Model (GLM) analysis it was found that group (patients or controls), and not serum folate, vitamin B12 and the T allele of MTHFR C677 polymorphism had significant effect on homocysteine levels. Thus a number of factors that may increase homocysteine levels were ruled out. Although it was not possible to obtain a complete data set for some factors (alcohol, smoking and caffeine consumption) (a weakness of the study), strengths included consecutive recruitment, minimisation of selection bias, good matching for age and gender between patients and controls, and the consideration of (serum) folate and (serum) vitamin B12 as potential confounding variables. A number of other studies have found significantly increased homocysteine levels in young patients compared with controls, particularly males. Most related studies favoured the homocysteine-psychosis link. The probability of symptomatic recovery is very high (80-90%) after treatment for first episode psychosis (Robinson et al., 1999) and delayed treatment, but prolonged duration of treatment is associated with poorer response in treatment and worse outcome (Malla & Norman, 2002). This justifies studying homocysteine levels and cognitive function in that first period of psychosis. This research offers evidence for the importance of serum homocysteine levels as showing involvement in the etiology of psychosis. Lowering homocysteine may have a beneficial effect on symptoms and cognitive dysfunction in psychotic illness. Two randomised controlled trials have demonstrated benefit in psychotic illness of giving folate and consequently reducing homocysteine.(Godfrey & Toone, 1990; Levine et al., 2006b). Benefits of taking folate were found in both trials for both cognition and psychotic symptoms. By reducing homocysteine levels early in the illness, some of the excess cardiovascular mortality may be prevented. Secondary prevention of CVD does not appear to influence outcome (Hermann, Herrmann, & Obeid, 2007), so the right time to intervene and reduce risk would appear to be early in the course of psychosis. Additionally, by lowering homocysteine cognitive functioning and psychotic symptoms may be improved (Levine et al., 2006b).
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ItemA prospective study of the relationship between stress, coping and the onset of psychosis in a high risk group( 2005-06)The experience of stress and associated coping responses are often described as playing an important role in the onset of schizophrenia and other psychotic disorders. Despite widespread acceptance of this model, there is little empirical evidence to support such a relationship. This is partly due to a lack of well-designed prospective studies of the onset of psychotic disorders that incorporate different aspects of the stress and coping process. The relatively recent development of validated and reliable criteria for identifying young people at high-risk (UHR) of developing psychosis has enabled the process of onset of psychotic illnesses to be studied more closely than was previously possible. It has also opened the way to the development and evaluation of preventive interventions. This longitudinal study aimed to compare the experiences of stress and coping between a UHR cohort (N = 143) and a group of young people without mental health concerns (HC group, N = 32). In addition, the contribution of stress and coping in the development of acute psychosis in a subgroup of the UHR cohort (UHR-P, n = 18) was also investigated.